Abstract AIDS is a major health problem in the world with more than 36 million people living with HIV infection. HIV can invade the central nervous system (CNS) infecting resident macrophages, microglial cells, and astrocytes leading to neurologic complications. Although the use of highly active antiretroviral therapy (HAART) has led to a strong reduction of HAD incidence, the prevalenceofminorHADANDHANDstillremainsacommonprobleminAIDSpatients.Natural Killer(NK)cellsplayacriticalroleinimmuneresponsestoCNSinjury.NKcellactivitycontrols CNS autoimmunity and inflammation by their ability to kill proinflammatory microglia. NK cells may also impact CNS physiology by secreting IFN-?. Astrocytes are intimately involved in immunological and inflammatory events occurring in the CNS. The impact of NK-astrocyte interactionsinregulationofimmuneresponseinthebrainispoorlyunderstood.Ourpreliminary data showed that Natural Cytotoxicity Receptor (NCR) NKp44 interacts with a novel ligand expressedonastrocytes.ThereisacriticalneedtounderstandthefunctionalsignificanceofNK cellsintheCNSduringHIVinfectionandtheirinteractionswithastrocytes.Characterizationof this novel ligand for NKp44 could lead to new insight into NK cell mediated immune response against HIV infection in the CNS. In this study, using mammalian expression cloning we will clonethisligandusingNKp44-Fcfusionprotein.Wewillalsoinvestigatethefunctionaloutcome ofNKp44ligandexpressedonastrocytesinteractionwithNKp44inregulatingimmuneresponse mediatedbyNKcells.Here,wewilldeterminetheeffectofNKp44receptor/ligandinteractionon NKcellcytolyticfunctionandIFN-?production.Characterizationofthisnovelligandcouldlead tonewinsightintoNKcellmediatedimmuneresponseagainstHIVinfectionintheCNS.